Abstract

Myelin sheaths play important roles in neuronal functions. In the central nervous system (CNS), the myelin is formed by oligodendrocytes (OLs), which are differentiated from oligodendrocyte precursor cells (OPCs). In CNS demyelinating disorders such as multiple sclerosis (MS), the myelin sheaths are damaged and the remyelination process is hindered. Small molecule drugs that promote OPC to OL differentiation and remyelination may provide a new way to treat these demyelinating diseases. Here we report that donepezil, an acetylcholinesterase inhibitor (AChEI) developed for the treatment of Alzheimer's disease (AD), significantly promotes OPC to OL differentiation. Interestingly, other AChEIs, including huperzine A, rivastigmine, and tacrine, have no such effect, indicating that donepezil's effect in promoting OPC differentiation is not dependent on the inhibition of AChE. Donepezil also facilitates the formation of myelin sheaths in OPC-DRG neuron co-culture. More interestingly, donepezil also promotes the repair of the myelin sheaths in vivo and provides significant therapeutic effect in a cuprizone-mediated demyelination animal model. Donepezil is a drug that has been used to treat AD safely for many years; our findings suggest that it might be repurposed to treat CNS demyelinating diseases such as MS by promoting OPC to OL differentiation and remyelination.